Combination of a 4-pyrimidinesulfamide derivative with an sglt-2 inhibitor for the treatment of endothelin related diseases

Abstract

The present invention concerns the compound aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide: and its use as endothelin receptor antagonist, in combination with an SGLT-2 inhibitor. The invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said SGLT-2 inhibitor. The invention further relates to such pharmaceutical compositions comprising crystalline forms of aprocitentan.

1 - 17 . (canceled) 
     
     
         18 . A method
 for the prophylaxis or treatment of chronic kidney disease (CKD), including CKD caused by/associated with hypertension, or caused by/associated with diabetes; acute or chronic renal failure; diabetic nephropathy; or glomerulonephritis;   for the prophylaxis or treatment of diabetes or diabetes related diseases including diabetic arteriopathy, diabetic retinopathy, or diabetic vasculopathy; diabetic complications; for reducing the risk of developing a major cardiovascular event in patients who have diabetes, including patients who have diabetes that is accompanied by at least one other cardiovascular risk factor; or for the prophylaxis or treatment of diabetic foot ulcers and/or for reducing the risk of lower extremity amputations in patients who have diabetes;   for the prophylaxis or treatment of heart failure including systolic heart failure and diastolic heart failure; for reducing the risk of developing a major cardiovascular event in patients who are at cardiovascular risk; or for the prophylaxis or treatment of ischemic heart diseases including angina pectoris, coronary diseases, and myocardial ischemia; cardiac insufficiency; or diastolic dysfunction;   for the treatment of hypertension including resistant hypertension;   for the prophylaxis or treatment of atherosclerosis; or peripheral arterial obliterant disease including chronic peripheral arteriopathy;   for the prophylaxis or treatment of digital ulcers; or   for the prophylaxis or treatment of connective tissue diseases;   
       said method comprising the administration of a pharmaceutically effective amount of aprocitentan, or of a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein aprocitentan is administered in combination with an SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method
 for the prophylaxis or treatment of chronic kidney disease (CKD) caused by/associated with hypertension;   for the prophylaxis or treatment of diabetic kidney disease (DKD);   for the prophylaxis or treatment of chronic renal failure caused by/associated with hypertension and/or caused by/associated with diabetes; diabetic nephropathy; or glomerulonephritis caused by/associated with hypertension;   for reducing the risk of developing a major cardiovascular event in patients who have diabetes, including in patients who have diabetes that is accompanied by at least one other cardiovascular risk factor;   for the prophylaxis or treatment of diabetic foot ulcers and/or for reducing the risk of lower extremity amputations in patients who have diabetes; or   for the prophylaxis or treatment of heart failure including systolic heart failure and diastolic heart failure;   
       said method comprising the administration of a pharmaceutically effective amount of aprocitentan, or of a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein aprocitentan is administered in combination with an SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 18 , wherein the method is
 for treatment of chronic kidney disease (CKD) caused by/associated with hypertension,   for treatment of diabetic kidney disease (DKD) associated, in addition, with hypertension,   for reducing the risk of developing a major cardiovascular event in patients who have diabetes, wherein said diabetes that is accompanied by at least one other cardiovascular risk factor comprising hypertension; or   for treatment of hypertension including resistant hypertension.   
     
     
         21 . The method according to  claim 18 , wherein the method is for treatment of chronic kidney disease (CKD) caused by/associated with hypertension. 
     
     
         22 . The method according to  claim 18 , wherein the method is for treatment of diabetic kidney disease (DKD) associated, in addition, with hypertension. 
     
     
         23 . The method according to  claim 18 , wherein the method is for treatment of hypertension including resistant hypertension. 
     
     
         24 . The method according to  claim 18 , wherein said SGLT-2 inhibitor is atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, or tofogliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method according to  claim 18 , wherein said SGLT-2 inhibitor is canagliflozin, dapagliflozin, or empagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method according to  claim 18 , wherein said SGLT-2 inhibitor is canagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method according to  claim 18 , wherein said SGLT-2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method according to  claim 18 , wherein said SGLT-2 inhibitor is empagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method according to  claim 18 , wherein aprocitentan, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan. 
     
     
         30 . The method according to  claim 25 , wherein aprocitentan, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan; and
 canagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 50 to 400 mg per day of canagliflozin;   dapagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 1 to 20 mg per day of dapagliflozin; and   empagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 5 to 50 mg per day of empagliflozin.   
     
     
         31 . The method according to  claim 20 , wherein said SGLT-2 inhibitor is atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, or tofogliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method according to  claim 20 , wherein said SGLT-2 inhibitor is canagliflozin, dapagliflozin, or empagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method according to  claim 20 , wherein said SGLT-2 inhibitor is canagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method according to  claim 20 , wherein said SGLT-2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method according to  claim 20 , wherein said SGLT-2 inhibitor is empagliflozin, or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method according to  claim 20 , wherein aprocitentan, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan. 
     
     
         37 . The method according to  claim 32 , wherein aprocitentan, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan; and
 canagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 50 to 400 mg per day of canagliflozin;   dapagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 1 to 20 mg per day of dapagliflozin; and   empagliflozin, or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 5 to 50 mg per day of empagliflozin.